The production of pharmaceutical solid dosage forms involves a multistage operation. It requires between six and eight unit processes, such as charging of raw materials, milling, granulation, drying, blending, compression, coating and packaging. In some of these processes the treated material contents may change their properties. For instance, in a granulation process, solid materials may be mixed with a liquid, wherein the liquid bounding state, the liquid contents, the temperature and density of the mixture is changing as the process progresses. In a drying process the liquid content is reduced, and the density and the temperature may change during the process. A coating process may be performed either in a fluidised bed wherein particles, so-called nuclei, are sprayed with a specific coating liquid, or by passing the particles through a spray dust of said liquid, or by other generally used coating techniques, such as melting, aggregation etc., wherein the material properties may change as the coating process progresses.
The quality of the different processes depends on different physical and/or chemical properties of the materials used in the process, such as chemical composition, local inhomogeneities, physical and chemical homogeneity, density, mechanical properties, static parameters, modulus, tensile strength, elongation at break, compression, ductility, viscoelastic parameters, morphology, macro- and microscopic properties, amorphous and/or crystallinity, permeability, porosity, aggregation, wettability, degree of coalescence/maturity, stability and ability to resist chemical and/or physical degradation.
There are also other properties not listed above. In order to keep the quality of the material at the end of a unit process, it is desirable to control that process.
In an industrial plant for manufacturing pharmaceutical products, selected process parameters are monitored and controlled to achieve a desired quality of the finished product. Such process parameters could include, for example, the motor output in the granulation vessel, the flow rate of water into the granulation vessel, the pressure in the coating vessel, the temperature in the drying vessel, the flow rate and temperature of gas and coating liquid supplied to the coating vessel, etc. However, the influence of such global process parameters on the processes, and ultimately on the properties of the end product, is known only from experience in a specific plant. Thus, a processing scheme is developed for each specific plant by extensive testing. When, for example, the size or shape of the vessels are changed during scaling up of the process the local environment of the materials in the vessels may be altered. This calls for time-consuming measurements and adjustments in order to regain the same properties of the end product.
There is also a need to improve existing manufacturing processes as well as to improve existing plants. Today, this is a laborious task since the influence of any change in the process scheme or the plant design on the end product has to be investigated by extensive testing, often in full scale. The same applies to the development of new products, for example when new types of material (solid or liquid) should be used.
For instance, in a high-shear granulation process it is common to monitor the process by measuring the power consumption of the motor which drives an agitator, impeller or propeller or some other mixing means inside the high-shear granulation vessel. That kind of monitoring is an indirect measurement which only provides information about the general state of the process. For developing process control parameters, the personnel may study many granulation processes, wherein different amounts of liquid has been added and with different power consumptions, and then choose one which provided a satisfactory granulation product. The parameters used for obtaining the satisfactory granulation, will consequently be used for future granulations. In other words, this known procedure is empirical and only provides an indirect control of the process. Thus, one limitation of the prior art methods in pharmaceutical process lies in their calibration. Apart from this laborious way to calibrate a process, in particular a granulation process, and the rather imprecise monitoring of measuring the power consumption for determining whether the granulation has reached a desired state, there is also a scaling-up problem. Scaling-up is not straight forward and therefore needs to be empirically adjusted. The power consumption pattern may be quite different in a full-scale high-shear granulation vessel in an manufacturing plant compared to a small vessel used in a laboratory. Scale-up issues are discussed in e.g. in A. Faure, P. York, R. C. Rowe, Process control and scale-up of pharmaceutical wet granulation processes: a review, European Journal of Pharmaceutics and Biopharmaceutics 52 (2001) 269-277.
An example of power consumption measurement may be obtained from an article by Gabriele Betz, Pascale Junker Bürgin and Hans Leuenberger, Power consumption measurement and temperature recording during granulation, International Journal of Pharmaceutics, Volume 272, Issues 1-2, 2004, pp. 137-149. The article and the references therein explain and demonstrate the application of power consumption measurements for indirect end-point determination of the high-shear granulation process. It also describes how additional measurements of the temperature may complement the process understanding. Another article on this subject is written by M. Bardin, P. C. Knight, J. P. K. Seville: On control of particle size distribution in granulation using high-shear mixers, Powder Technology 140 (2004), 169-175. It describes the indirect link of the particle size distribution during granulation to the power consumption, and also demonstrates the shortcomings of the method for coarse powders where no relation was directly identified.
In summary, even though there are methods of monitoring pharmaceutical processes, such as a high-shear granulation process, there still remains improvements to be made for alleviating the drawbacks of the above methods.